title: New combination of pharmacophoric elements of potent σ₁ ligands: design, synthesis and σ receptor affinity of aminoethyl substituted tetrahydrobenzothiophenes.
abstract: The aminoethyl substituted tetrahydrobenzothiophenes 4 resulted from combination of the pharmacophoric elements of the potent σ₁ ligands 2 and 3. The aminoethyl substituted tetrahydrobenzothiophenes 4 were prepared in an 8-step synthesis starting with thiophene. Whereas the σ₁ affinity of the N-benzyl derivative 4a is in the medium nanomolar range (Ki = 49 nM), the analogous N-cyclohexylmethyl derivative 4d exhibits low nanomolar affinity (Ki = 5.0 nM). The reduced σ₁ affinity and σ₂/σ₁ selectivity of tetrahydrobenzothiophenes 4 compared to analogous spirocyclic piperidines 3 is attributed to the increased conformational flexibility of the aminoethyl side chain.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms, Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Dipak
authors.initials: D
authors.lastname: Harel
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D001921:Brain; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006168:Guinea Pigs; D008024:Ligands; D008099:Liver / Q000737:chemistry; D015394:Molecular Structure; D051381:Rats; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D008024:Ligands; D017480:Receptors, sigma; D013876:Thiophenes
keywords: Combination of pharmacophoric elements; Conformational flexibility; Horner–Wittig reaction; Tetrahydrobenzothiophenes; σ(1) ligands